New compounds for the treatment and/or prevention of parasitic diseases and method of production of thereof

Patent metadata

Field	Value
Publication number	US-2016168084-A1
Application number	US-201414906206-A
Country	US
Kind code	A1
Filing date	Jul 17, 2014
Priority date	Jul 18, 2013
Publication date	Jun 16, 2016
Grant date	—

Abstract

Disclosed are new compounds for treating, preventing or inhibiting a parasitic disease, preferably toxoplasmosis in a subject, the method for preparing thereof.

First claim

1 . Compound of formula (I′):

wherein:
n is a natural number chosen from 0, 1 and 2,
X is chosen from

Ar is an aryl or an arylalkyl, said aryl or arylalkyl being substituted by a halogen, which is a fluor atom, a thiazolyl, or a group chosen from: —OR 1 in meta position, —R 2 —O—R 1 , wherein R 1 represents a C 1 -C 8 -alkyl, which is eventually substituted by a halogen, R 2 represents a C 1 -C 8 alkylene group eventually substituted by a halogen,

or a pharmaceutically acceptable salt thereof.

2 . Compound of formula (I′) according to claim 1 , wherein Ar is chosen from
i) a phenyl substituted at the meta-, para- or ortho-position by a fluor or a thiazolyl, or
ii) a benzyl substituted at the meta-position by an C1 to C4 alkoxy group.

3 . Compound of formula (I′) according to claim 1 , wherein
n is a natural number chosen from 0, 1 and 2,
X is chosen from

Ar is a benzyl substituted at the meta-position by a methoxy group.

said compound corresponding to formula (Ia):

4 . Compound of formula (Ia) according to claim 3 ,
wherein either n is 0 and X is

said compound corresponding to formula (Ia1),
or wherein n is 1 and X is

said compound corresponding to formula (Ia2).

5 . Compound of formula (I′) according to claim 1 , wherein
n is a natural number chosen from 0, 1 and 2,
X is chosen from

Ar is a phenyl substituted at the meta-position by a fluor,

said compound corresponding to formula (Ib):

6 . Compound of formula (Ib) according to claim 5 ,
wherein either n is 1 and X is

said compound corresponding to formula (Ib1),
or wherein n is 0 and X is

said compound corresponding to formula (Ib2),
or wherein n is 1 and X is

said compound corresponding to formula (Ib3),
or wherein n is 0 and X is

said compound corresponding to formula (Ib4).

7 . Compound of formula (I′) according to claim 1 , wherein
n is a natural number chosen from 0, 1 and 2,
X is chosen from

Ar is a phenyl substituted at para postion by

said compound corresponding to formula (Ic):

8 . Compound of formula (Ic) according to claim 7 ,
wherein either n is 1 and X is

said compound corresponding to formula (Ic1),
or wherein n is 0 and X is

said compound corresponding to formula (Ic2).

9 . A method for treating, inhibiting or preventing a parasitic disease in a mammalian subject, including human, cat or dog, comprising applying an effective amount of the compound of formula (I′) of claim 1 in the form of a pharmaceutical drug.

10 . The method of claim 9 , wherein the parasitic disease is caused by a protozoan parasite of the family of the Trypanosomatidae selected from the genus Trypanosoma or the genus Leishmania , or the parasite Toxoplasma gondii.

11 . A method for treating toxoplasmosis, comprising applying an effective amount of the compound of formula (Ia1) of claim 4 in the form of a pharmaceutical drug.

12 . A pharmaceutical composition comprising a compound of formula (I′) according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable excipient.

13 . A pharmaceutical composition comprising:
a compound of formula (I′) according claim 1 , or a pharmaceutically acceptable salt thereof, and at least one anti-parasitic compound, selected from the group comprising: miltefosin, antimony based drugs, like meglumine antimoniate or sodium stibogluconate, amphotericin B, benzimidazol, nifurtimox, paromomycin, pentamidin and its derivatives, arsenic derivatives, melarsoprol and difluoromethylornithin.

14 . Method for preparing a compound of formula (I′) according to claim 1 , comprising the following steps:
(i) the reaction between a compound of formula II′

wherein n is a natural number chosen from 0, 1 and 2,
with a compound of formula III′: Ar—X—Cl, wherein
X is chosen from

Ar is an aryl or an arylalkyl, said aryl or arylalkyl being substituted by a halogen, which is a fluor atom, a thiazolyl, or a group chosen from: —OR 1 in meta position, —R 2 —O—R 1 , wherein R 1 represents a C 1 -C 8 -alkyl, which is eventually substituted by a halogen, R 2 represents a C 1 -C 8 alkylene group eventually substituted by a halogen,

to obtain a compound of formula IV′

wherein:
n is a natural number chosen from 0, 1 and 2,
X is chosen from

Ar is an aryl or an arylalkyl, said aryl or arylalkyl being substituted by a halogen, which is a fluor atom, a thiazolyl, or a group chosen from: —OR 1 in meta position, —R 2 —O—R 1 , wherein R 1 represents a C 1 -C 8 -alkyl, which is eventually substituted by a halogen, R 2 represents a C 1 -C 8 alkylene group eventually substituted by a halogen,

ii) the reaction between the compound of formula IV′ and a base to obtain a compound of formula V′

wherein n, X and Ar respectively has the same definition of that for formula IV′, said compound of formula V′ is eventually acidified,
and M + represents a metallic cation;
(iii) the reaction between the compound of formula V′ and hydroxylamine to obtain the compound of formula I′.

15 . A method for treating, inhibiting or preventing a parasitic disease in a mammalian sub

Assignees

• Inst Rech Developpement Ird
• Univ Montpellier
• Centre Nat Rech Scient

Inventors

• Sereno Denis
• Labesse Gilles
• Guichou Jean-Francois Alexandre
• Loeuillet Corinne
• Garcia Deborah Isabelle
• Delbecq Stephane

Classifications

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• C07C311/19

  to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups · CPC title

• C07C311/21

  having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C259/06 Primary

  having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07D277/30

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title